Hexahydropyrazinobenz- or -pyrido-oxazepines carrying an oxygen-containing substituent and use thereof in the treatment of 5-ht2c-dependent disorders

Abstract

The present invention relates to compound of formula (I) (I) wherein the variables are as defined in the claims and the description. The invention further relates to a pharmaceutical composition containing such compounds, to their use as modulators, especially agonists or partial agonists, of the 5-HT 2C receptor, to their use for preparing a medicament for the prevention or treatment of conditions and disorders which respond to the modulation of 5-HT 2C receptor, and to methods for preventing or treating conditions and disorders which respond to the modulation of 5-HT 2C receptor.

1 - 29 . (canceled) 
     
     
         30 . A compound of formula (I) 
       
         
           
           
               
               
           
         
         wherein 
         X is CR 7  or N; 
         R 1  is selected from the group consisting of hydrogen, methyl, deuterated methyl, and fluorinated methyl; 
         R 2a , R 2b , R 3a  and R 3b , independently of each other, are selected from the group consisting of hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 3 -C 6 -cycloalkyl, and C 3 -C 6 -halocycloalkyl; or
 R 2a  and R 3a , or R 2b  and R 3b , together with the carbon atom they are bound to, form a 3-membered saturated carbocyclic ring; or 
 R 1  and R 2a , if present, form together a group —[CH 2 ] s —, where s is 1, 2, 3 or 4; or 
 R 1  and R 2b  form together a group —[CH 2 ] s —, where s is 1, 2, 3 or 4; 
 
         R 4 , R 5 , R 6  and R 7 , independently of each other, are selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 4 -alkyl, fluorinated C 1 -C 4 -alkyl, C 1 -C 4 -hydroxyalkyl, C 2 -C 4 -alkenyl, fluorinated C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl, fluorinated C 2 -C 4 -alkynyl, C 3 -C 6 -cycloalkyl, fluorinated C 3 -C 6 -cycloalkyl, C 1 -C 4 -alkoxy, fluorinated C 1 -C 4 -alkoxy, C 1 -C 4 -alkylthio, and fluorinated C 1 -C 4 -alkylthio; 
         R 8  is selected from the group consisting of hydrogen, C 1 -C 4 -alkyl, fluorinated C 1 -C 4 -alkyl, and C 1 -C 4 -hydroxyalkyl; 
         n is 0 or 1; 
         or pharmaceutically acceptable salt thereof. 
       
     
     
         31 . The compound of  claim 30 , wherein n is 0 and R 1  is selected from the group consisting of hydrogen, methyl, and deuterated methyl. 
     
     
         32 . The compound of  claim 31 , wherein n is 0 and R 1  is methyl. 
     
     
         33 . The compound of  claim 30 , wherein n is 0 and R 2b  and R 3b , independently of each other, are selected from the group consisting of hydrogen, methyl, CHF 2 , CF 3 , and cyclopropyl. 
     
     
         34 . The compound of  claim 33 , wherein n is 0 and R 2b  and R 3b  are hydrogen. 
     
     
         35 . The compound as claimed in  claim 30 , wherein n is 0, R 1  and R 2b  form together a group —[CH 2 ] s —, wherein s is 1, 2, 3 or 4; or n is 1, R 1  and R 2a  form together a group —[CH 2 ] s —, wherein s is 1, 2, 3 or 4. 
     
     
         36 . The compound as claimed in  claim 35 , wherein n is 0, R1 and R2b form together a group —[CH2]s-, wherein s is 2, and R3b is hydrogen. 
     
     
         37 . The compound as claimed in  claim 35 , wherein n is 1, R 1  and R 2a  form together a group —CH 2 —, and R 2b , R 3a  and R 3b  are hydrogen. 
     
     
         38 . The compound as claimed in  claim 34 , wherein R 4  is selected from the group consisting of fluorine, chlorine, cyano, methyl, CHF 2 , CF 3 , and C 3 -alkynyl. 
     
     
         39 . The compound as claimed in  claim 38 , wherein X is CR 7 . 
     
     
         40 . The compound as claimed in  claim 36  wherein R 4  is selected from the group consisting of fluorine, chlorine, cyano, methyl, CHF 2 , CF 3 , and C 3 -alkynyl. 
     
     
         41 . The compound as claimed in  claim 40 , wherein X is CR 7 . 
     
     
         42 . The compound as claimed in  claim 37 , wherein R 4  is selected from the group consisting of fluorine, chlorine, cyano, methyl, CHF 2 , CF 3 , and C 3 -alkynyl. 
     
     
         43 . The compound as claimed in  claim 42 , wherein X is CR 7 . 
     
     
         44 . The compound of formula (I.cis) 
       
         
           
           
               
               
           
         
         wherein X, R 1 , R 2a , R 2b , R 3a , R 3b , R 4 , R 5 , R 6 , R 8  and n are as defined in  claim 30 . 
       
     
     
         45 . A compound selected from the group consisting of:
 (4aR,6S)-8-chloro-6-(methoxymethyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazepine;   (4aR,6R)-8-chloro-6-(methoxymethyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazepine;   (4aR,6S)-6-(methoxymethyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazepine;   (4aR,6R)-6-(methoxymethyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazepine;   (4aR,6S)-8-chloro-9-fluoro-6-(methoxymethyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazepine;   (4aR,6S)-8-(difluoromethyl)-6-(methoxymethyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazepine;   (4aR,6S)-8-chloro-10-fluoro-6-(methoxymethyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazepine;   (4aR,6S)-10-fluoro-6-(methoxymethyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazepine;   (4aR,6S)-8-(difluoromethyl)-10-fluoro-6-(methoxymethyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazepine;   (4aR,6S)-10-chloro-6-(methoxymethyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazepine;   (4aR,6S)-8,10-difluoro-6-(methoxymethyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazepine;   (4aR,6S)-6-(methoxymethyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazepine-8-carbonitrile;   (4aR,6S)-10-fluoro-6-(methoxymethyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazepine-8-carbonitrile;   [(4aR,6S)-8-chloro-2,3,4,4a,5,6-hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazepin-6-yl]methanol;   (4aR,6S)-8-chloro-11-fluoro-6-(methoxymethyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazepine;   (4aR,6S)-8-chloro-10,11-difluoro-6-(methoxymethyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazepine;   [(4aR,6S)-8-chloro-10-fluoro-2,3,4,4a,5,6-hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazepin-6-yl]methanol;   (4aR,6S)-8,10,11-trifluoro-6-(methoxymethyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazepine;   (4aR,6S)-8-chloro-10-fluoro-6-(trideuteriomethoxymethyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazepine;   [(4aR,6S)-8-chloro-10,11-difluoro-2,3,4,4a,5,6-hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazepin-6-yl]methanol;   (4aR,6S)-10,11-difluoro-6-(methoxymethyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazepine;   (4aR,6S)-10-fluoro-6-(methoxymethyl)-8-(trifluoromethyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazepine;   [(4aR,6S)-8-(difluoromethyl)-10-fluoro-2,3,4,4a,5,6-hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazepin-6-yl]methanol;   (4aR,6S)-8-chloro-6-(difluoromethoxymethyl)-10-fluoro-2,3,4,4a,5,6-hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazepine;   (4aR,6S)-10-chloro-8-fluoro-6-(methoxymethyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazepine;   (4aR,6S)-8-(difluoromethyl)-10,11-difluoro-6-(methoxymethyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazepine;   (6S,7aR)-4-(difluoromethyl)-6-(methoxymethyl)-7,7a,8,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepine 2,2,2-trifluoroacetic acid;   (4aR,6S)-10,11-difluoro-6-(methoxymethyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazepine-8-carbonitrile;   (4aR,6S)-8-(difluoromethyl)-11-fluoro-10-methoxy-6-(methoxymethyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazepine;   (4aR,6S)-8-fluoro-6-(methoxymethyl)-9-methyl-2,3,4,4a,5,6-hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazepine;   (4aR,6S)-10-chloro-9-fluoro-6-(methoxymethyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazepine;   (4aR,6R)-8-(difluoromethyl)-10-fluoro-6-(methoxymethyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazepine;   (4aR,6S)-8-fluoro-6-(methoxymethyl)-10-methyl-2,3,4,4a,5,6-hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazepine;   (4aR,6S)-8-ethynyl-10-fluoro-6-(methoxymethyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazepine;   (4aR,6R)-8-chloro-10-fluoro-6-(methoxymethyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazepine;   (4aR,6S)-10-ethynyl-8-fluoro-6-(methoxymethyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazepine;   (4aR,6R)-8-chloro-10,11-difluoro-6-(methoxymethyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazepine;   (4aR,6S)-8-chloro-9,10-difluoro-6-(methoxymethyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazepine;   [(4aR,6S)-8-fluoro-9-methyl-2,3,4,4a,5,6-hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazepin-6-yl]methanol;   (4aR,6S)-8-ethynyl-10,11-difluoro-6-(methoxymethyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazepine;   (4aR,6S)-10-fluoro-6-(methoxymethyl)-8-methyl-2,3,4,4a,5,6-hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazepine;   (4aR,6S)-8-(difluoromethoxy)-6-(methoxymethyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazepine;   (4aR,6S)-10-(difluoromethoxy)-8-fluoro-6-(methoxymethyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazepine;   (4aR,6S)-8-chloro-10-methoxy-6-(methoxymethyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazepine;   (4aR,6S)-8-chloro-6-(methoxymethyl)-10-(trifluoromethyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazepine;   [(4aR,6S)-8-chloro-10-(trifluoromethyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazepin-6-yl]methanol;   (4aR,6S)-9,10,11-trifluoro-6-(methoxymethyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazepine;   (4aR,6S)-8-cyclopropyl-6-(methoxymethyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazepine;   (4aR,6S)-8-cyclopropyl-10-fluoro-6-(methoxymethyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazepine;   (4aR,6S)-8-fluoro-6-(methoxymethyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazepine;   (4aR,6S)-9-fluoro-6-(methoxymethyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazepine;   (4aR,6S)-8,10-dichloro-6-(methoxymethyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazepine;   (4aR,6S)-8-chloro-10,11-difluoro-9-methoxy-6-(methoxymethyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazepine;   (4aR,6S)-11-fluoro-6-(methoxymethyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazepine;   (4aR,6S)-8-chloro-9,10,11-trifluoro-6-(methoxymethyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazepine; and   (4aR,6S)-10,11-difluoro-6-(methoxymethyl)-8-(trifluoromethyl)-2,3,4,4a,5,6-hexahydro-1H-benzo[b]pyrazino[1,2-d][1,4]oxazepine;   or a pharmaceutically acceptable salt thereof.   
     
     
         46 . A compound as claimed in  claim 45 , selected from the group consisting of:
 (4aR,6S)-8-Chloro-10-fluoro-6-(methoxymethyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazepine;   (4aR,6S)-8-(Difluoromethyl)-10-fluoro-6-(methoxymethyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazepine;   (4aR,6S)-8-Chloro-10,11-difluoro-6-(methoxymethyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazepine; and   (4aR,6S)-8-Chloro-9,10,11-trifluoro-6-(methoxymethyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazino[2,1-d][1,5]benzoxazepine;   or a pharmaceutically acceptable salt thereof.   
     
     
         47 . A pharmaceutical composition comprising a therapeutically effective amount of at least one compound as claimed in  claim 30 , or a pharmaceutically acceptable salt thereof, in combination with at least one pharmaceutically acceptable carrier. 
     
     
         48 . A method for treating disorders which respond to the modulation of the 5-HT2c receptor, which method comprises administering to a subject in need thereof at least one compound as defined in  claim 30 , or a pharmaceutically acceptable salt thereof.